291 The dosage of somatostatin used in this study is different from what is usually used for octreotide, the synthetic analog (100 to 400 }1g/day); use of octreotide in the therapy of fistulas, however, remains investiga-
patients.
tional. It is important to note that the number of fistulas healed/closed in both groups was similar. Somatostatin did not result in an increase in the number of fistulas healed. Similarly, the fistulas included in this study were of modest output. However, somatostatin treatment resulted in accelerated fistula closure and reduced morbidity in somatostatin-treated patients who healed their fistulas, compared with control group patients. Three of the four patients who were crossed over to the somatostatin-treated group at 15 days healed their fistulas. In approaching the patient with a gastrointestinal fistula, patients need to be selected who need a surgical procedure because of distal obstruction, tract epithelialization, and other underlying causes. Candidates are then selected for trial of TPN therapy without surgical treatment. In this group of patients, it appears that somatostatin therapy can significantly shorten the time of fistula closure and decrease patient morbidity, perhaps by decreasing the length of hospitalization. Finally, it is important to note that somatostatin use is associated with significant side effects, ie, hyperglycemia. Nonetheless, this study and other previously published studies suggest that the use of somatostatin or its synthetic analog octreotide has a beneficial effect in the treatment of uncomplicated gastrointestinal fistulas.
has been examined. 4 One of the early concerns regarding use of TPN in patients with cancer is the effect of administration of concentrated intravenous nutrient solutions on tumor growth rate. Although studies in animal tumor models have demonstrated preferential use of intravenous protein and energy substrates by tumors, in vivo studies in humans have failed to provide similar results. In this study, 18 nutritionally matched patients with localized rectal carcinoma were randomly divided into two groups. Both groups received a low-residue diet and bowel preparation on days 3 and 2 before the operation. Oral intake was discontinued in both groups on day 1 before the operation. At that time, one group was given intravenous fluid (fasted group) and the other group a lipid-based TPN regimen (fed group). Both groups received a 20-hour infusion. Procedures for measuring the rate of tumor protein synthesis began at the end of the infusion immediately before the operation. Patients received an intravenous bolus of C]leucine 13 [ after having blood samples drawn for determining the natural baseline concentration of the isotope in plasma proteins. Sixty to ninety minutes after injection of the isotope, patients were anesthetized and proctoscopic tumor biopsies were performed. The fractional rate of
HARRY C. SAX, MD University of Rochester Rochester, NY REFERENCES
was determined by an equation 5 publication of the authors. The investigators also performed an in vitro study using malignant colorectal cancer cells isolated from six
tumor
protein synthesis
used in
an
earlier
patients who received the
same
TPN
regimen
come
WV, Coutsofides T, Steiger F:
Factors
the outof treatment of small bowel cutaneous fistula. World J Surg
influencing
7:481-488, 1983 Therapy of enterocutaneous fistulas. Contemp Surg 29:104-108, 1986 3. Di Constanzo J, Cano N, Martin J, et al: Treatment of external gastrointestinal fistulas by a combination of total parenteral nutrition and somatostatin. JPEN 11:465-470, 1987
2. Fischer JE:
Stimulation of Protein Synthesis in Human Tumors by Parenteral Nutrition: Evidence for Modulation of Tumor Growth S. D. HEYS, K. G. M. PARK, M. A. MCNURLAN, British Journal of Surgery 78:483-487, 1991
ET AL
Abstract: The use of total parenteral nutrition (TPN) in patients with cancer has received much attention. 1-3 Use of perioperative TPN in patients undergoing tumor resections and its use in patients receiving cancer chemotherapy
the fed
and immediately after the 20-hour infusion. After the malignant tumor cells were incubated in each patient’s serum, protein synthetic rates were determined by measuring the incorporation of H[ 3 ]phenylalanine into cellular protein. Patients in the fed group demonstrated
1. Fazio
as
group to rule out any contribution to protein synthesis by nontumor cells. Blood samples were taken before TPN
a
significantly
higher rate of tumor protein synthesis than did those patients in the fasted group (42.7 ± 3.5%/day vs 22.6 ± 1.9%/day, p .002). Similarly, the rate of protein synthesis, expressed per gram of RNA, was also significantly increased in the group receiving TPN. The tumor RNA concentration, however, was not significantly affected by feeding. This prompted the authors to conclude that the increase in protein synthesis resulted from an increase in ribosomal synthetic activity instead of an increase in =
the total number of ribosomes. The measurements presented above were carried out on total tumor protein with limitations because of the heterogeneity of the tumor cell population. To confirm that it was the malignant cells that responded to the nutrient intake changes, in vitro experiments were carried out using homogeneous populations of cancer cells. The results demonstrated a significant increase in incorporation of labeled phenylalanine into protein when colorectal tumor cells were incubated with autologous serum from a patient taken after 24 hours of TPN administration compared with fasting. There was a mean increase of 81% in protein synthesis when fed patient’s serum was used (p < .02) compared with serum obtained during fasting. These results provide additional evidence
Downloaded from pen.sagepub.com at SIMON FRASER LIBRARY on June 7, 2015
292
that exogenous nutrients
can
modulate human tumor
growth. Comment: This report is one of several recent articles that address the impact of concentrated intravenous nutrients on human malignant tumors. It demonstrates that protein synthesis in colorectal carcinomas is significantly higher in patients receiving TPN compared with fasted patients. Many previous trials performed in a variety of tumorbearing animal models have reported stimulation of tumor growth after TPN, as measured by tumor/carcass weight ratios, isotopic amino acid uptake, and other markers of protein synthesis. In general, these studies used rapidly growing tumors that grew to proportions not consistent with what is usually seen in humans. Before this investigation, studies of tumor-bearing humans reported no differences in rates of tumor protein synthesis in patients who received TPN when compared with patients who did not receive TPN. Although the study design in this study is similar to that used on previous investigations of protein metabolism in tumorbearing patients,’,’ a notable difference is in the method used to measure the rate of protein synthesis. The investigators have used the &dquo;flooding-dose&dquo; technique, in which a large amount of unlabeled amino acid is given together with the isotope as a bolus infusion. Other investigators have used the &dquo;constant-infusion&dquo; method, in which only isotope is continuously infused during the study period. The authors of this study have published several prior reports suggesting that the flooding-dose method is a more precise technique for determining the rate of protein synthesis in vivo.8 However, Pomposelli and coworkers9 reported significantly higher rates of protein synthesis with the floodingdose method as compared with the continuous-infusion method in non-tumor-bearing rats. Other differences in study methods such as the length of TPN infusion and
the method of tissue collection may have contributed to the contrasting results reported in this study. However, the authors’ conclusion is further substantiated by the results of their in vitro experiments. Although the findings of this study are in agreement with those of many previous studies using tumor-bearing animals, their results are in conflict with findings of earlier studies in humans with cancer. Further work is needed to determine the tumor response to nutrients in humans and the role of nutrient modulation in designing future oncologic
therapeutic regimens. TODD W. MATTOX, PHARMD H. Lee Moffitt Cancer Center and Research Institute Tampa, Fla REFERENCES 1.
Steiger E, Oram-Smith J, Miller E, et al: Effects of nutrition on tumor growth and tolerance to chemotherapy. J Surg Res 18:455461, 1975
2. Kishi T, Iwasawa
tumor-bearing
Y, Hiroshi I,
rats to oral
or
et al: Nutritional responses of intravenous feeding. JPEN 6:295-
300, 1982 Popp MB, Wagner SC, Britto OJ: Host and tumor responses to increasing levels of nutritional support. Surgery 94:300-308, 1983 4. Nixon DW, Moffitt S, Lawson DH, et al: Total parenteral nutrition as an adjunct to chemotherapy of metastatic colorectal cancer. Cancer Treat Rep 65:121-128, 1981 5. McNurlan MA, Tomkins AM, Garlick PJ. The effect of starvation on the rate of protein synthesis in rat liver and small intestine. Biochem J 178:373-379, 1979 6. Mullen JL, Buzby G, Gertner MH, et al: Protein synthesis dynamics in human gastrointestinal malignancies. Surgery 87:331-338, 3.
1980 7. Shaw 8.
9.
JHF, Humberstone DA. Cancer: A metabolic parasite. Br J Surg 75:1262, 1988 Garlick PJ, McNurlan MA, Preedy VR: A rapid and convenient technique for measuring the rate of protein synthesis in tissues by injection of [ H]phenylalanine. Biochem J 192:719-230, 1980 3 Pomposelli JJ, Palombo JD, Hamawy KJ, et al: Comparison of different techniques for estimating protein synthesis in vivo in healthy and bacteremic rats. Biochem J 226:37-42, 1985
Downloaded from pen.sagepub.com at SIMON FRASER LIBRARY on June 7, 2015
patients.
tional. It is important to note that the number of fistulas healed/closed in both groups was similar. Somatostatin did not result in an increase in the number of fistulas healed. Similarly, the fistulas included in this study were of modest output. However, somatostatin treatment resulted in accelerated fistula closure and reduced morbidity in somatostatin-treated patients who healed their fistulas, compared with control group patients. Three of the four patients who were crossed over to the somatostatin-treated group at 15 days healed their fistulas. In approaching the patient with a gastrointestinal fistula, patients need to be selected who need a surgical procedure because of distal obstruction, tract epithelialization, and other underlying causes. Candidates are then selected for trial of TPN therapy without surgical treatment. In this group of patients, it appears that somatostatin therapy can significantly shorten the time of fistula closure and decrease patient morbidity, perhaps by decreasing the length of hospitalization. Finally, it is important to note that somatostatin use is associated with significant side effects, ie, hyperglycemia. Nonetheless, this study and other previously published studies suggest that the use of somatostatin or its synthetic analog octreotide has a beneficial effect in the treatment of uncomplicated gastrointestinal fistulas.
has been examined. 4 One of the early concerns regarding use of TPN in patients with cancer is the effect of administration of concentrated intravenous nutrient solutions on tumor growth rate. Although studies in animal tumor models have demonstrated preferential use of intravenous protein and energy substrates by tumors, in vivo studies in humans have failed to provide similar results. In this study, 18 nutritionally matched patients with localized rectal carcinoma were randomly divided into two groups. Both groups received a low-residue diet and bowel preparation on days 3 and 2 before the operation. Oral intake was discontinued in both groups on day 1 before the operation. At that time, one group was given intravenous fluid (fasted group) and the other group a lipid-based TPN regimen (fed group). Both groups received a 20-hour infusion. Procedures for measuring the rate of tumor protein synthesis began at the end of the infusion immediately before the operation. Patients received an intravenous bolus of C]leucine 13 [ after having blood samples drawn for determining the natural baseline concentration of the isotope in plasma proteins. Sixty to ninety minutes after injection of the isotope, patients were anesthetized and proctoscopic tumor biopsies were performed. The fractional rate of
HARRY C. SAX, MD University of Rochester Rochester, NY REFERENCES
was determined by an equation 5 publication of the authors. The investigators also performed an in vitro study using malignant colorectal cancer cells isolated from six
tumor
protein synthesis
used in
an
earlier
patients who received the
same
TPN
regimen
come
WV, Coutsofides T, Steiger F:
Factors
the outof treatment of small bowel cutaneous fistula. World J Surg
influencing
7:481-488, 1983 Therapy of enterocutaneous fistulas. Contemp Surg 29:104-108, 1986 3. Di Constanzo J, Cano N, Martin J, et al: Treatment of external gastrointestinal fistulas by a combination of total parenteral nutrition and somatostatin. JPEN 11:465-470, 1987
2. Fischer JE:
Stimulation of Protein Synthesis in Human Tumors by Parenteral Nutrition: Evidence for Modulation of Tumor Growth S. D. HEYS, K. G. M. PARK, M. A. MCNURLAN, British Journal of Surgery 78:483-487, 1991
ET AL
Abstract: The use of total parenteral nutrition (TPN) in patients with cancer has received much attention. 1-3 Use of perioperative TPN in patients undergoing tumor resections and its use in patients receiving cancer chemotherapy
the fed
and immediately after the 20-hour infusion. After the malignant tumor cells were incubated in each patient’s serum, protein synthetic rates were determined by measuring the incorporation of H[ 3 ]phenylalanine into cellular protein. Patients in the fed group demonstrated
1. Fazio
as
group to rule out any contribution to protein synthesis by nontumor cells. Blood samples were taken before TPN
a
significantly
higher rate of tumor protein synthesis than did those patients in the fasted group (42.7 ± 3.5%/day vs 22.6 ± 1.9%/day, p .002). Similarly, the rate of protein synthesis, expressed per gram of RNA, was also significantly increased in the group receiving TPN. The tumor RNA concentration, however, was not significantly affected by feeding. This prompted the authors to conclude that the increase in protein synthesis resulted from an increase in ribosomal synthetic activity instead of an increase in =
the total number of ribosomes. The measurements presented above were carried out on total tumor protein with limitations because of the heterogeneity of the tumor cell population. To confirm that it was the malignant cells that responded to the nutrient intake changes, in vitro experiments were carried out using homogeneous populations of cancer cells. The results demonstrated a significant increase in incorporation of labeled phenylalanine into protein when colorectal tumor cells were incubated with autologous serum from a patient taken after 24 hours of TPN administration compared with fasting. There was a mean increase of 81% in protein synthesis when fed patient’s serum was used (p < .02) compared with serum obtained during fasting. These results provide additional evidence
Downloaded from pen.sagepub.com at SIMON FRASER LIBRARY on June 7, 2015
292
that exogenous nutrients
can
modulate human tumor
growth. Comment: This report is one of several recent articles that address the impact of concentrated intravenous nutrients on human malignant tumors. It demonstrates that protein synthesis in colorectal carcinomas is significantly higher in patients receiving TPN compared with fasted patients. Many previous trials performed in a variety of tumorbearing animal models have reported stimulation of tumor growth after TPN, as measured by tumor/carcass weight ratios, isotopic amino acid uptake, and other markers of protein synthesis. In general, these studies used rapidly growing tumors that grew to proportions not consistent with what is usually seen in humans. Before this investigation, studies of tumor-bearing humans reported no differences in rates of tumor protein synthesis in patients who received TPN when compared with patients who did not receive TPN. Although the study design in this study is similar to that used on previous investigations of protein metabolism in tumorbearing patients,’,’ a notable difference is in the method used to measure the rate of protein synthesis. The investigators have used the &dquo;flooding-dose&dquo; technique, in which a large amount of unlabeled amino acid is given together with the isotope as a bolus infusion. Other investigators have used the &dquo;constant-infusion&dquo; method, in which only isotope is continuously infused during the study period. The authors of this study have published several prior reports suggesting that the flooding-dose method is a more precise technique for determining the rate of protein synthesis in vivo.8 However, Pomposelli and coworkers9 reported significantly higher rates of protein synthesis with the floodingdose method as compared with the continuous-infusion method in non-tumor-bearing rats. Other differences in study methods such as the length of TPN infusion and
the method of tissue collection may have contributed to the contrasting results reported in this study. However, the authors’ conclusion is further substantiated by the results of their in vitro experiments. Although the findings of this study are in agreement with those of many previous studies using tumor-bearing animals, their results are in conflict with findings of earlier studies in humans with cancer. Further work is needed to determine the tumor response to nutrients in humans and the role of nutrient modulation in designing future oncologic
therapeutic regimens. TODD W. MATTOX, PHARMD H. Lee Moffitt Cancer Center and Research Institute Tampa, Fla REFERENCES 1.
Steiger E, Oram-Smith J, Miller E, et al: Effects of nutrition on tumor growth and tolerance to chemotherapy. J Surg Res 18:455461, 1975
2. Kishi T, Iwasawa
tumor-bearing
Y, Hiroshi I,
rats to oral
or
et al: Nutritional responses of intravenous feeding. JPEN 6:295-
300, 1982 Popp MB, Wagner SC, Britto OJ: Host and tumor responses to increasing levels of nutritional support. Surgery 94:300-308, 1983 4. Nixon DW, Moffitt S, Lawson DH, et al: Total parenteral nutrition as an adjunct to chemotherapy of metastatic colorectal cancer. Cancer Treat Rep 65:121-128, 1981 5. McNurlan MA, Tomkins AM, Garlick PJ. The effect of starvation on the rate of protein synthesis in rat liver and small intestine. Biochem J 178:373-379, 1979 6. Mullen JL, Buzby G, Gertner MH, et al: Protein synthesis dynamics in human gastrointestinal malignancies. Surgery 87:331-338, 3.
1980 7. Shaw 8.
9.
JHF, Humberstone DA. Cancer: A metabolic parasite. Br J Surg 75:1262, 1988 Garlick PJ, McNurlan MA, Preedy VR: A rapid and convenient technique for measuring the rate of protein synthesis in tissues by injection of [ H]phenylalanine. Biochem J 192:719-230, 1980 3 Pomposelli JJ, Palombo JD, Hamawy KJ, et al: Comparison of different techniques for estimating protein synthesis in vivo in healthy and bacteremic rats. Biochem J 226:37-42, 1985
Downloaded from pen.sagepub.com at SIMON FRASER LIBRARY on June 7, 2015
